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Orphan Nuclear Receptors in Breast Cancer Pathogenesis and Therapeutic Response

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Orphan Nuclear Receptors in Breast Cancer Pathogenesis and Therapeutic Response Endocrine-Related Cancer (2010) 17 R213–R231 REVIEW Orphan nuclear receptors in breast cancer pathogenesis and therapeutic response Rebecca B Riggins1, Mary M Mazzotta1, Omar Z Maniya1 and Robert Clarke1,2 1Lombardi Comprehensive Cancer Center and Department of Oncology and 2Department of Physiology and Biophysics, Georgetown University School of Medicine, 3970 Reservoir Road NW, Washington, District of Columbia 20057, USA (Correspondence should be addressed to R Clarke; Email: [email protected]) Abstract Nuclear receptors comprise a large family of highly conserved transcription factors that regulate many key processes in normal and neoplastic tissues. Most nuclear receptors share a common, highly conserved domain structure that includes a carboxy-terminal ligand-binding domain. However, a subgroup of this gene family is known as the orphan nuclear receptors because to date there are no known natural ligands that regulate their activity. Many of the 25 nuclear receptors classified as orphan play critical roles in embryonic development, metabolism, and the regulation of circadian rhythm. Here, we review the emerging role(s) of orphan nuclear receptors in breast cancer, with a particular focus on two of the estrogen-related receptors (ERRa and ERRg) and several others implicated in clinical outcome and response or resistance to cytotoxic or endocrine therapies, including the chicken ovalbumin upstream promoter transcription factors, nerve growth factor-induced B, DAX-1, liver receptor homolog-1, and retinoic acid-related orphan receptor a. We also propose that a clearer understanding of the function of orphan nuclear receptors in mammary gland development and normal mammary tissues could significantly improve our ability to diagnose, treat, and prevent breast cancer. Endocrine-Related Cancer (2010) 17 R213–R231 What is an orphan nuclear receptor? region, on chromosome X, gene 1 (DAX-1, NR0B1) Members of the nuclear receptor superfamily are some and small heterodimerization partner (SHP, NR0B2) of the most abundant regulators of gene expression in lack a classical DNA-binding domain (DBD), and higher eukaryotes. These DNA-binding transcription cannot act alone to bind DNA (Burris et al. 1996, Seol factors play essential roles in key biological processes et al. 1996). The number of nuclear receptors classified from embryonic development to differentiation, and as orphans has decreased over the years as new ligands their dysregulation has been widely studied in many have been discovered. Two such ‘adopted orphans’ are different pathologies including cancer (Mangelsdorf the retinoid X receptors (RXRs) and the peroxisome et al. 1995, Robinson-Rechavi et al. 2003, Novac & proliferator-activated receptors (PPARs), which were Heinzel 2004, Jeong & Mangelsdorf 2009). initially considered to be orphans but have been firmly Of the 48 members of the human nuclear receptor in the category of liganded receptors for some time. superfamily, 25 are currently considered to be orphan RXRs and PPARs, along with several other formerly nuclear receptors (Benoit et al. 2006; Table 1) because orphaned nuclear receptors, form a group now referred they have no known ligand. Most of these 25 receptors to as natural or nutrient sensors that bind 9-cis retinoic adhere to the classical domain structure that typifies acid, oleic, and linoleic acids (Francis et al. 2003, ligand-regulated nuclear receptors (discussed in more Benoit et al. 2004). detail below), with two notable exceptions. Dosage- What constitutes an orphan receptor is still the sensitive sex reversal, adrenal hypoplasia critical subject of some debate. An example of the lingering Endocrine-Related Cancer (2010) 17 R213–R231 Downloaded from Bioscientifica.comDOI: 10.1677/ERC-10-0058 at 10/02/2021 01:12:41AM 1351–0088/10/017–R213 q 2010 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.orgvia free access R B Riggins et al.: Orphan nuclear receptors in breast cancer Table 1 Orphan nuclear receptors in breast cancer Gene symbols Common name Select ligand (s) mRNA overexpression in human breast cancera NR0B1 DAX-1 GSE2109, GSE3744, GSE1477, GSE1561 NR0B2 SHP GSE9014 NR1D1 Rev-Erba Heme GSE1378, GSE9014, GSE8977, GSE5949, GSE5460, GSE2109 NR1D2 Rev-Erbb Heme GSE2109, GSE3971, GSE10087, GSE1379, GSE5460, GSE3281, GSE3893 NR1F1 RORa Cholesterol GSE9014, GSE5460, GSE6861, GSE3744, GSE3893, derivatives GSE5764, GSE1477 NR1F2 RORb GSE3744, GSE9014, GSE5364 NR1F3 RORg GSE2109, GSE1477, GSE10843, GSE5460, GSE9014, GSE5764 NR2A1 HNF4-a Fatty acids GSE9014, GSE10843, GSE5720, GSE5764, GSE8977, GSE6861, GSE2109, GSE3744, GSE7390 NR2A2 HNF4-g Fatty acids GSE1561, GSE3744, GSE9014 NR2C1 TR2 GSE3744, GSE8977, GSE5847, GSE7390 NR2C2 TR4 GSE3744, GSE5460, GSE2109, GSE1477, GSE9014 NR2E1 TLX GSE7390, GSE3744, GSE2109 NR2E3 PNR GSE5364, GSE2109, GSE10843, GSE1561, GSE5460 NR2F1 COUP-TFI GSE5460, GSE2109, GSE1561, GSE3971, GSE9014 NR2F2 COUP-TFII GSE5364, GSE3193, GSE5460, GSE2109, GSE10843, GSE5720, GSE9014, GSE7390, GSE5764, GSE1561, GSE5949, GSE3971, GSE1379 NR2F6 EAR2 GSE2109, GSE10843, GSE3971, GSE5364, GSE10087, GSE1561, GSE3193, GSE3744, GSE5460, GSE1477, GSE4382, GSE5720, GSE1378, GSE5847 NR3B1 ERRa Isoflavones, DES, GSE3971, GSE2109, GSE10087, GSE10843, GSE7390, chlordane GSE9014, GSE1561, GSE1477, GSE1378, GSE5764, GSE5460 NR3B2 ERRb Isoflavones, DES, GSE5364, GSE10843, GSE6861, GSE5460, GSE2109, 4HT GSE1378, GSE9014, GSE1379, GSE5764 NR3B3 ERRg Isoflavones, DES, GSE2109, GSE9014, GSE1561, GSE5460, GSE7390, 4HT GSE10087, GSE1379 NR4A1 NGFI-B GSE10843, GSE1477, GSE5364, GSE9014, GSE3281, GSE5460, GSE2109 NR4A2 NURR1 GSE9014, GSE5460, GSE2109, GSE3281, GSE5364, GSE3971, GSE7390 NR4A3 NOR1 GSE2109, GSE1379, GSE5460, GSE3893, GSE5847, GSE1561, GSE5720, GSE8977, GSE9014 NR5A1 SF-1 Phospholipids GSE5460, GSE9014, GSE8977, GSE3744 NR5A2 LRH-1 Phospholipids GSE2109, GSE5847, GSE5764, GSE8977, GSE5460, GSE1561 NR6A1 GCNF GSE10843, GSE5847, GSE5460, GSE1561, GSE2109, GSE5764 DES, diethylstilbestrol; 4HT, 4-hydroxytamoxifen. aGSE identification numbers denote publicly available gene expression studies from gene expression omnibus (GEO). For each study, expression of the relevant nuclear receptor is significantly increased in breast cancer versus normal mammary tissue (P%0.05, pair-wise t-test). controversy is that orphan nuclear receptors like Nuclear receptor structure and function steroidogenic factor-1 (SF1, NR5A1) and hepatocyte As a group, most nuclear receptors share a common, nuclear factor-4 (HNF4, NR2A1 and NR2A2) have highly conserved domain structure (Fig. 1). At the been shown to bind phospholipids and fatty acids amino-terminus, the activation function-1 (AF1) respectively (Wisely et al. 2002, Li et al. 2005). domain is a highly divergent region that assists in However, because the physiological and/or functional regulating the transcriptional activity of nuclear relevance of these interactions remain unclear, SF1 receptors independent from ligand binding (Kumar & and HNF4 are still considered to be orphan Litwack 2009). The AF1 domain is one of the two nuclear receptors. major sites for the binding of nuclear receptor Downloaded from Bioscientifica.com at 10/02/2021 01:12:41AM via free access R214 www.endocrinology-journals.org Endocrine-Related Cancer (2010) 17 R213–R231 AF1 CTE AF2 Nuclear receptor DBDs contain a short stretch of v amino acids downstream of the two zinc fingers known N-term DBD Hinge LBD as the carboxy-terminal extension (CTE; Claessens & Co-regulator binding NLS Ligand binding Gewirth 2004). The CTE is present in ligand-regulated Co-regulator binding Dimerization nuclear receptors like the estrogen receptors Response element binding Dimerization (ERs; Schultz et al. 2002), androgen receptor (AR; Schoenmakers et al. 1999), and the vitamin D receptor Figure 1 Nuclear receptor domain structure. AF1, activation (Hsieh et al. 1999). However, orphan nuclear receptors function-1; DBD, DNA-binding domain; CTE, carboxy-terminal such as estrogen-related receptor b (ERRb, ESRRB, extension; NLS, nuclear localization sequence; LBD, ligand- binding domain; AF2, activation function-2. NR3B1) that bind a single half-site rely heavily on the A box of the CTE (which contains a conserved glycine–arginine motif) to permit DNA binding in coregulators, which include coactivator and corepressor the minor groove (Gearhart et al. 2003). In addition, proteins that can positively or negatively impact residues C-terminal to the A box form intramolecular transcriptional activity respectively; it is also an interactions with the rest of the DBD; together, these important site of posttranslational modification, includ- interactions serve to stabilize the binding of ERRb and ing phosphorylation and the addition of small several other orphan nuclear receptors to DNA. ubiquitin-like modifier proteins (SUMOylation; Taki- The carboxy-terminal ligand-binding domain (LBD) moto et al. 2003, Cheng et al. 2007, Zhang et al. 2007, and the AF2 domain are essential for the regulation of Tamasi et al. 2008, Garza et al. 2010). Much less is nuclear receptor transcriptional activity by mediating known about the AF1 domain as compared with other ligand and receptor interactions and coregulator binding; regions of nuclear receptors. One key reason is that the in some cases, these regions also participate in receptor AF1 domain has a high level of intrinsic disorder (ID; dimerization (Chandra et al. 2008). Upon the engage- Kumar & Litwack 2009), although this is not the only ment
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